Abstract
ObjectiveChronic Helicobacter pylori (H. pylori) infection promotes non-cardia gastric cancer. Some mouse models suggest that bone marrow derived cells (BMDC) contribute to Helicobacter-associated gastric carcinogenesis. We determined whether this increased susceptibility to Helicobacter-induced gastric carcinogenesis of p27-deficient mice is dependent upon their p27-null BMDC or their p27-null gastric epithelial cells.DesignFemale mice (recipients) were irradiated and transplanted with BMDC from male donors. Wild type (WT) mice in group 1 (control) received BMDC from male GFP-transgenic mice. Female WT and p27 KO mice were engrafted with male p27KO mice BMDC (Group 2) or GFP-transgenic WT BMDC (Group 3). Recipients were infected with H. pylori SS1 for one year.ResultsMice lacking p27 in either the BM pool or gastric epithelium developed significantly more advanced gastric pathology, including high-grade dysplasia. Co-staining of donor BMDC in dysplastic gastric glands was confirmed by immunofluorescence. Gastric expression of IL-1 beta protein was reduced in groups 2 and 3 (p < 0.05 vs control) whereas expression of IFN-γ and chemokines MIP-1 beta, MIG, IP-10 and RANTES in group 2 were significantly higher than group 3.ConclusionsBoth bone marrow-derived and gastric epithelial cells contribute to the increased gastric cancer susceptibility of p27-deficient H. pylori-infected mice.
Highlights
Gastric expression of IL-1 beta protein was reduced in groups 2 and 3 (p < 0.05 vs control) whereas expression of IFN-γ and chemokines MIP-1 beta, Monokine induced by gamma interferon (MIG), interferon gammainduced protein 10 (IP-10) and RANTES in group 2 were significantly higher than group 3
Both bone marrow-derived and gastric epithelial cells contribute to the increased gastric cancer susceptibility of p27-deficient H. pylori-infected mice
Chronic Helicobacter infection triggered the migration of bone marrow-derived cells (BMDC) to the stomach, where they gave rise to neoplastic gastric epithelial cells and progressed to gastric adenocarcinoma via the classic changes described by Dr Correa
Summary
Gastric cancer is the fifth most common neoplasm and the third leading cause of cancer death worldwide. [1] Most cases of gastric cancer are attributable to persistent chronic infection by Helicobacter pylori (H. pylori), including almost 90% of cases of non-cardia gastric cancer. [2] Since H. pylori was designated a definite gastric carcinogen in 1994, [3] the pathogenesis of H. pylori infection has been extensively studied, but exactly how this bacterium and/or the associated gastric inflammatory response contributes to gastric carcinogenesis remains poorly defined.Gastric malignancy usually develops after a multistep, decades-long process, as proposed by Correa in 1975. [4] In this “conventional model”, the epithelial cells and glands of the gastric mucosa undergo progressive histological change, as confirmed by numerous murine studies. [5,6,7] Additional steps to this model were proposed by Houghton et al in 2004, [8] based upon H. felis infection in wild type C57BL/6 mice. [1] Most cases of gastric cancer are attributable to persistent chronic infection by Helicobacter pylori (H. pylori), including almost 90% of cases of non-cardia gastric cancer. Chronic Helicobacter infection triggered the migration of bone marrow-derived cells (BMDC) to the stomach, where they gave rise to neoplastic gastric epithelial cells and progressed to gastric adenocarcinoma via the classic changes described by Dr Correa. Donor and recipient mice in three experimental groups. All of the mice have C57BL/6 background and all donors are males, recipients are females. Support for the “BMDC model” has come from similar experiments by Varon and colleagues using mice infected by H. pylori Sydney Strain 1 (SS1), [9] in which BMDC were identified in approximately 25% of dysplastic gastric lesions, which are thought to be precursors of gastric adenocarcinoma
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